Concept: Aspergillus fumigatus
Azole resistance in Aspergillus fumigatus: can we retain the clinical use of mold-active antifungal azoles?
- Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
- Published over 5 years ago
Azole resistance in Aspergillus fumigatus has emerged into a global health problem. Although the number of cases of azole-resistant aspergillosis is still limited, resistance mechanisms continue to emerge thereby threatening the role of the azole class in the management of Aspergillus diseases. The majority of cases of azole-resistant disease are due to resistant A. fumigatus originating from the environment. Patient management is difficult due to the absence of patient risk factors, delayed diagnosis and limited treatment options, resulting in poor treatment outcome. International and collaborative efforts are required to understand how resistance develops in the environment in order to allow effective measures to be implemented aimed at retaining the use of azoles both for food production and human medicine.
In recent years, Aspergillus species are reported frequently as aetiological agents of fungal keratitis in tropical countries such as India. Our aim was to evaluate the epidemiological features of Aspergillus keratitis cases over a 3-year period in a tertiary eye care hospital and to determine the antifungal susceptibilities of the causative agents. This study included culture proven Aspergillus keratitis cases diagnosed between September 2005 and August 2008. Data including prevalence, predisposing factors and demography were recorded, the isolates were identified by morphological and molecular methods and the minimum inhibitory concentration values of antifungal agents towards the isolates were determined by the microdilution method. Two hundred Aspergillus isolates were identified among 1737 culture proven cases. Most of the aspergilli (75%) proved to be A. flavus, followed by A. fumigatus (11.5%). Sixteen (8%) isolates belonged to species that are recently identified causative agents of mycotic keratitis. Most of the infected patients (88%) were adults ranging from 21 to 70 years of age. Co-existing ocular disease was confirmed in 16.5% of the patients. Econazole, clotrimazole and ketoconazole were notably active against A. flavus. Aspergillus keratitis is a significant problem in patients with ocular lesions in South-Indian States, warranting early diagnosis and initiation of specific antifungal therapy to improve outcome.
Aspergillosis is one of the most common causes of death in captive birds. Aspergillus fumigatus accounts for approximately 95 % of aspergillosis cases and Aspergillus flavus is the second most frequent organism associated with avian infections. In the present study, the fungi were grown from avian clinical samples (post-mortem lung material) and environmental samples (eggs, food and litter). Microsatellite markers were used to type seven clinical avian isolates and 22 environmental isolates of A. flavus. A. flavus was the only species (28 % prevalence) detected in the avian clinical isolates, whereas this species ranked third (19 %) after members of the genera Penicillium (39 %) and Cladosporium (21 %) in the environmental samples. Upon microsatellite analysis, five to eight distinct alleles were detected for each marker. The marker with the highest discriminatory power had eight alleles and a 0.852 D value. The combination of all six markers yielded a 0.991 D value with 25 distinct genotypes. One clinical avian isolate (lung biopsy) and one environmental isolate (egg) shared the same genotype. Microsatellite typing of A. flavus grown from avian and environmental samples displayed an excellent discriminatory power and 100 % reproducibility. This study showed a clustering of clinical and environmental isolates, which were clearly separated. Based upon these results, aspergillosis in birds may be induced by a great diversity of isolates.
Effusin A (1), a spirobicyclic N,O-acetal derivative with an unprecedented 3',3a',5',6'-tetrahydrospiro[piperazine-2,2'-pyrano[2,3,4-de]chromene] ring system, and a spiro-polyketide-diketopiperazine hybrid dihydrocryptoechinulin D (2) were isolated from a mangrove rhizosphere soil derived fungus, Aspergillus effuses H1-1. Their structures were determined by detailed spectroscopic analysis. Effusin A (1) and dihydrocryptoechinulin D (2) occurred as racemates, the enantiomers of which were separated and characterized by online HPLC-ECD analysis and their absolute configurations were determined by the solution TDDFT ECD calculation approach. The cytotoxic effects of 1 and 2 were preliminarily evaluated and 2 showed potent activity on P388 cells with an IC(50) value of 1.83 μM. The target of racemic 2 was also investigated and the (12R,28S,31S)-2 enantiomer showed selectivity against topoisomerase I.
Voriconazole is a first-line agent for the treatment of invasive pulmonary aspergillosis (IPA). There are increasing reports of Aspergillus fumigatus isolates with reduced susceptibility to voriconazole.
IgE sensitization to Aspergillus fumigatus and a positive sputum fungal culture result are common in patients with refractory asthma. It is not clear whether these patients would benefit from antifungal treatment.
OBJECTIVE: The aim of the present study was to assess the anti-Aspergillus activity of culture filtrate of Streptomyces sp. VITSTK7 and biologically synthesized Ag2O/Ag nanoparticles using the culture filtrate of VITSTK7. MATERIAL AND METHODS: Silver nanoparticles were synthesized by biological reduction of silver nitrate using culture filtrate of Streptomyces sp. VITSTK7. The synthesized nanopaticles were characterized for surface plasma resonance peak, X-ray diffraction patterns, shape and size distribution. Inhibition of mycelial growth was used as an index of anti-Aspergillus activity of synthesized nanoparticles. RESULTS: The synthesized nanoparticles were spherical shaped and monodespersive in nature and showed a single surface plasma resonance peak at 420nm. X-ray diffraction patterns displayed typical peaks of crystalline silver oxide and size distribution histograms indicated production of 20-60-nm-size nanoparticles with average size of 35.2nm. The synthesized nanoparticles showed anti-Aspergillus activity against Aspergillus niger, Aspergillus flavus and Aspergillus fumigatus with antifungal index in the range of 62-75%. CONCLUSION: Thus the bioconversion of Ag2O/Ag nanoparticles by Streptomyces sp. VITSTK7 could be employed to control Aspergillus pathogenesis. The results of this study suggest that the green synthesis of Ag2O/Ag nanoparticles using marine Streptomyces sp. VITSTK7 yielded 27.9nm sized particles with potential to act against pathogenic Aspergillus species.
Pulmonary aspergilloma is a chronic fungal infection that has a high mortality when hemoptysis occurs. Surgery is the treatment of choice, but patients often have severe physiologic impairment putting them at risk for significant surgical morbidity and mortality. We present the case of a 63-year-old woman with a large aspergilloma, unfit for surgery due to medical reasons. The aspergilloma was enlarging, with progression of the patient’s symptoms of anorexia, cough, chest discomfort, and hemoptysis. Bronchoscopy revealed an airway leading into a cavity with a large fungal ball. Biopsy confirmed Aspergillus fumigatus. Using flexible and rigid bronchoscopy, the aspergilloma was mechanically removed. Eighteen months later the patient reported no hemoptysis, reduced pain and cough, significant weight gain, and improved appetite, with no recurrence of the aspergilloma on repeat imaging. To our knowledge, this is the first reported case of bronchoscopic removal of a large cavitary aspergilloma. This important new treatment modality provides a viable alternative therapy for this potentially life-threatening problem.
- Proceedings of the National Academy of Sciences of the United States of America
- Published about 4 years ago
There is an important medical need for new antifungal agents with novel mechanisms of action to treat the increasing number of patients with life-threatening systemic fungal disease and to overcome the growing problem of resistance to current therapies. F901318, the leading representative of a novel class of drug, the orotomides, is an antifungal drug in clinical development that demonstrates excellent potency against a broad range of dimorphic and filamentous fungi. In vitro susceptibility testing of F901318 against more than 100 strains from the four main pathogenic Aspergillus spp. revealed minimal inhibitory concentrations of ≤0.06 µg/mL-greater potency than the leading antifungal classes. An investigation into the mechanism of action of F901318 found that it acts via inhibition of the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) in a fungal-specific manner. Homology modeling of Aspergillus fumigatus DHODH has identified a predicted binding mode of the inhibitor and important interacting amino acid residues. In a murine pulmonary model of aspergillosis, F901318 displays in vivo efficacy against a strain of A. fumigatus sensitive to the azole class of antifungals and a strain displaying an azole-resistant phenotype. F901318 is currently in late Phase 1 clinical trials, offering hope that the antifungal armamentarium can be expanded to include a class of agent with a mechanism of action distinct from currently marketed antifungals.
Aspergillus fumigatus is a conditional pathogen and the major cause of life threatening invasive aspergillosis (IA) in immunocompromised patients. The early and rapid detection of A. fumigatus infection is still a major challenge. In this study, the new member of fungal annexin family annexin C4 was chosen as the target to design loop-mediated isothermal amplification (LAMP) assays for the rapid, specific, and sensitive detection of A. fumigatus. Evaluation on the specificity of the LAMP developed showed that no false-positive results were observed for the 22 non-A. fumigatus strains including five species of Aspergillus genus. Its detection limit was approximately 10 copies per reaction in reference plasmids, with higher sensitivity than that of real-time quantitative PCR (qPCR) at 10(2) copies for the same target. A total of 69 clinical patients comprised of probable IA (n = 14) and possible IA infection patients (n = 55) were subjected to the LAMP assay developed, and 14 probable IA patients (100%) and 34 possible IA patients (61.82%) were detected positive. When the detection using the LAMP developed was compared with that using qPCR in 69 clinical samples, LAMP demonstrated a sensitivity of 89.19% and the concordant rate of two methods was up to 72.46%. Accordingly, a valuable LAMP assay for rapid, specific, and simple detection of A. fumigatus in clinical testing has been developed.